藥學科技二報告：
Scifinder
及 Innovation 應用
主題：Diclofenac 相關合成與專利資料
課程：藥學科技二
指導老師：吳建德老師
系級：藥學系三年級
班別：Ｄ班
學號：B303098176
姓名：洪雅庭
一、動機：
在最初兩次的藥學科技二的課程中，吳老師安排我們上機，講解並教導我們
去運用 Scifinder 和 Innovation 這兩個平台來搜尋資料。Scifinder 資料廣泛，內容
豐富且包含了各種面向，是十分好用的文獻搜尋資源，而 Innovation 則是便於專
利的查詢。此兩個平台都是未來極有可能用得上的便利資源，而透過這次報告也
讓我們有了實際練習的機會。
在藥物化學課程中，授課的劉老師介紹到了 Diclofenac 這項藥品，使我立刻
想到了著名痠痛貼布廣告中的「大摳粉圓」的台詞，想說既然一直有耳聞，但是
以前並不清楚這個藥到底是做什麼用的，剛好配合這次的報告，於是 diclofenac
就成為了我的報告主題。
二、藥品介紹－Diclofenac
1.
為 Arylacetic acid Derivatives 的 NSAID(non-steroid anti-inflammatory
drugs)
2.
為目前最廣為使用的 NSAID 類藥品
3.
作用機轉和一般的 NSAID 有所不同，十分特別：
(1).
抑制 arachidonic acid cyclooxygenase system
(2).
抑制 lipoxygenase
(3).
抑制 arachidonic acid 的釋放和促進其再回收
三、Scifinder 搜尋過程
1.
一開始先在搜尋列直接打入 Diclofenac，但發現資料量過多，再鎖定近
十年的時間來篩選，但仍有超過 10000 筆資料，且內容不一定符合我想
要找的方向，所以改用結構繪圖去找：
2.
搜尋到了六百多筆資料：
3.
點入其中一篇：
4.
載下可能會用到的數篇文獻備用。
四、合成方法
搜尋資料的過程中發現 Dioclofenac 不止一種合成方式，而且也有許多文獻
顯示常常有研究利用 Dioclofenac 做結構上的修飾，研發新藥，以下節錄其中一
種的合成方式：（見下圖）
部分文獻內容(此文獻因為研究所需，有使用
11C
做標定)：
The method is based on the synthesis of a chlorinated precursor, namely the
2-[(2,6-dichlorophenyl)amino]benzyl chloride (3), which, by reaction with sodium [11C]cyanide
and successive hydrolysis, can be converted into [11C] diclofenac. The chlorinated precursor was
not commercially available: it was prepared optimizing the synthesis described in the literature [3]. The sequence of reactions is reported in Scheme 1A. Reaction between 2-chlorobenzoic acid and 2,6- dichloroaniline produced 2-[(2,6-dichlorophenyl)amino] benzoic acid (1), which was then reduced with LiAlH4 to 2-[(2,6-dichlorophenyl)amino]benzyl alcohol (2). The alcohol
was chlorinated with thionyl chloride in pyridine to produce the precursor (3).
(1). Compound 1
2-Chlorobenzoic acid (52.5 g, 0.33 mol) and KOH (19.5 g, 0.35 mol) in 160 ml of 1-pentanol were heated at 100°C under stirring for 1 h. 2,6-Dichloroaniline (100 g, 0.65 mol) and copper powder (1.25 g, 0.02 mol) were then added after cooling, and the mixture was refluxed for 120 h. After cooling, a solution of Na2CO3 (54 g in 180 ml of water) was
added to the mixture. The organic layer was separated and the aqueous phase was extracted with pentanol. Organic phases were combined and concentrated HCl was added dropwise to precipitate a brown solid. The solid was filtered under vacuum, washed repeatedly with concentrated HCl and dried under vacuum. Pure compound 1 was obtained after crystallization from EtOH/H2O (50/50). The yield was 21%; mp 210°C–
212°C. 1H-NMR: δ (CDCl3) 6.3 (dd, 1H), 6.8 (dt, 1H), 7.1–7.5 (m, 4H), 8.1 (dd, 1H), 9.2
(s, 1H). HPLC (eluent B): retention time: 1.7 min.
(2). Compound 2
A solution of compound 1 (10 g, 35 mmol) in 80 ml of anhydrous THF was added dropwise to a suspension of LiAlH4 in 30 ml of anhydrous THF cooled at 5°C–15°C.
The resulting mixture was then heated and refluxed for 15 h under stirring. After cooling, 20 ml of water, 20 ml of 15% NaOH solution and 60 ml of water were carefully added at 0°C–5°C. The suspension was filtered, and the solid residue was washed on the filter with THF. The organic phase was concentrated under vacuum, and the resulting solid dissolved in ethyl acetate. The solution was washed with 2N Na2CO3 solution and saturated NaCl
solution. The organic phase was concentrated at reduced pressure. Ethyl ether was added to the residue and pure compound 2 was recovered adding petroleum ether to the solution. The yield was 67%; mp 108°C–110°C. 1H-NMR δ (CDCl3): 1.8 (bs, 1H), 4.8 (d, 2H) 6.4
(dd, 1H), 6.9 (dt, 1H), 7.1–7.3 (m, 4H), 7.4 (d, 1H). HPLC (eluent B): retention time: 2.9 min.
(3). Compound 3
A solution of compound 2 (7 g, 26 mmol) in 104 ml of dry diethyl ether and 10.4 ml of anhydrous pyridine was quickly added dropwise to a solution of 10.4 ml of SOCl2 in 56
ml of anhydrous pentane cooled at 0°C. The solution was stirred for 30 min at 0°C and then poured on ice. The mixture was extracted with 30 ml of 2N HCl and washed with 30 ml of 2N NaOH solution followed by 30 ml of water. The organic phase was filtered and dried over K2CO3, and the solvent evaporated at reduced pressure. Compound 3 was
recovered as yellow oil and used without further purification. Yield was 47%. 1H-NMR δ
(CDCl3): 4.6 (d, 2H) 6.4 (dd, 1H), 6.9 (dt, 1H), 7.1–7.3 (m, 4H), 7.4 (dd, 1H). HPLC
(eluent A): retention time: 8.8 min. Direct HPLC-MS identification of compound 3 was attempted with a triple quadrupole (Applied Biosystems Sciex API 4000) mass
spectrometer coupled with a Perkin Elmer Series 200 Micro HPLC system using MeOH as eluent. Under these conditions, we observed a quantitative conversion of the chloro derivative into the corresponding methoxy derivative (molecular peaks at m/ z=282 and m/z=284).
(4). 2-[(2,6-Dichlorophenyl)amino]phenyl]acetonitrile
Potassium cyanide (100 μg, 1.5 μmol) was added to a solution of 10 mg (33 μmol) of compound 3 in 500 μl of DMSO in a capped V-shaped vial. The mixture was heated at 40°C for 20 min. The solution was used in HPLC (eluent A) without purification of the product as comparison for compound 4. Retention time: 11.4 min; purity: 92%. (5). Sodium [11C]cyanide
[11C]CO2 was produced at the cyclotron and trapped into a stainless steel loop cooled with
liquid nitrogen. At the end of the delivery, the cooling bath was removed and [11C]CO2
was swept by a nitrogen stream (60 ml/min), mixed on-line with pure hydrogen (25 ml/min), and the mixture passed through an oven containing nickel kieselguhr heated at 485°C to achieve reduction to [11C]methane. [11C]methane was purified on-line passing
through a trap of magnesium perchlorate and one of ascarite before being mixed with ammonia gas (15 ml/min) and converted to H11CN in a furnace containing platinum wool
heated at 1000°C. H[11C] CN was recovered by bubbling in a V-shaped vial closed by a
screw cap and a silicon septum containing 500 μl of absolute ethanol, 25 μl of 1 M NaOH and 25 μl of 1.5 M KCN. The solvent was evaporated under nitrogen flow, and the resulting sodium [11C]cyanide solution was used without purification.
(6). 1-[11C]-2-{2-[(2,6-Dichlorophenyl)amino]phenyl]} acetonitrile (4)
Thirty milligrams (0.1 mmol) of compound 3 in 1.5 ml of DMSO was added to the vial containing Na11CN (2.5 mCi). The solution was heated at 110°C for 10 min under stirring. 11C-labeled compound 4 was not isolated. Radio- HPLC (eluent A) retention time: 11.3
min; radiochemical purity: 84%. (7). [11C]diclofenac sodium (5 )
The vial containing crude 11C-labeled compound 4 was added with 10N NaOH and 0.5 ml
of 30% H2O2, and the mixture was heated at 135°C for 10 min under stirring. 11C-labeled
compound 5 was identified on the basis of the HPLC features of the unlabeled compound and was obtained (N°=20) with a radiochemical yield of 43%±3.8. HPLC (eluent A): 7.9 min. Pure 11C-labeled compound 5 was obtained by HPLC in the same condition.
Radiochemical purity: 97%±4.2 (N°=20). No chemical impurities were detected (detection limit for cold diclofenac was 3 μg/ml UV/VIS at 254 nm)
(8). Final formulation
The formulation to be used for administration consisted of a non-pressurized sprayer. The same components of the sprayer (vial, seal and cap containing the piston) were received from the manufacturer. Before each experimental session, the amount of [11C]diclofenac
radioactivity (180±20 MBq, 100–200 μl according to radioactive concentration) was withdrawn from the bulk, placed into the sprayer vial and dried under gentle nitrogen stream for 1 min. The capping system was removed from a diclofenac sprayer formulation, and 3 ml of the preparation was withdrawn and transferred to the vial with the
radioactivity. The vial was closed again with the capping system, shaken and placed into a shielded container.
